Dynamically Crosslinked PEG Hydrogels Reveal a Critical Role of Viscoelasticity in Modulating Glioblastoma Fates and Drug Responses in 3D.
Advanced healthcare materials
Glioblastoma multiforme (GBM) is the most prevalent and aggressive brain tumor in adults. Hydrogels have been employed as 3D in-vitro culture models to elucidate how matrix cues such as stiffness and degradation drive GBM progression and drug responses. Recently, viscoelasticity has been identified as an important niche cue in regulating stem cell differentiation and morphogenesis in 3D. Brain is a viscoelastic tissue, yet how viscoelasticity modulates GBM fate and drug response remains largely unknown. Using dynamic hydrazone crosslinking chemistry, we report a poly(ethylene-glycol) (PEG)-based hydrogel system with brain-mimicking stiffness and tunable stress relaxation to interrogate the role of viscoelasticity on GBM fates in 3D. The hydrogel design allows tuning stress relaxation without changing stiffness, biochemical ligand density, or diffusion. Our results reveal that increasing stress relaxation promotes invasive GBM behavior, such as cell spreading, migration, and GBM stem-like cell (GSC) marker expression. Furthermore, increasing stress relaxation enhances GBM proliferation and drug sensitivity. Stress-relaxation induced changes on GBM fates and drug response were found to be mediated through the cytoskeleton andtransient receptor potential vanilloid-type 4 (TRPV4). These results highlight the importance of incorporating viscoelasticity into 3D in-vitro GBM models and provide novel insights into how viscoelasticity modulates GBM cell fates. This article is protected by copyright. All rights reserved.
View details for DOI 10.1002/adhm.202202147
View details for PubMedID 36239185
Matrix stiffness modulates patient-derived glioblastoma cell fates in 3D hydrogels.
Tissue engineering. Part A
Cancer progression is known to be accompanied by changes in tissue stiffness. Previous studies have primarily employed immortalized cell lines and 2D hydrogel substrates, which do not recapitulate the 3D tumor niche. How matrix stiffness affects patient-derived cancer cell fate in 3D remains unclear. Here we report a MMP-degradable poly(ethylene-glycol)-based hydrogel platform with brain-mimicking biochemical cues and tunable stiffness (40 to 26,600 Pa) for 3D culture of patient-derived glioblastoma xenograft (PDTX GBM) cells. Our results demonstrate that decreasing hydrogel stiffness enhanced PDTX GBM cell proliferation, and hydrogels with stiffnesses 240 Pa and below supported robust PDTX GBM cell spreading in 3D. PDTX GBM cells encapsulated in hydrogels demonstrated higher drug resistance than 2D control, and increasing hydrogel stiffness further enhanced drug resistance. Such 3D hydrogel platforms may provide a valuable tool for mechanistic studies of the role of niche cues in modulating cancer progression for different cancer types.
View details for DOI 10.1089/ten.TEA.2020.0110
View details for PubMedID 32731804
A comparative study of brain tumor cells from different age and anatomical locations using 3D biomimetic hydrogels.
Brain tumors exhibit vast genotypic and phenotypic diversity depending on patient age and anatomical location. Hydrogels hold great promise as 3D in vitro models for studying brain tumor biology and drug screening, yet previous studies were limited to adult glioblastoma cells, and most studies used immortalized cell lines. Here we report a hydrogel platform that supports the proliferation and invasion of patient-derived brain tumor cell cultures (PDCs) isolated from different patient age groups and anatomical locations. Hydrogel stiffness was tuned by varying poly(ethylene-glycol) concentration. Cell adhesive peptide (CGRDS), hyaluronic acid, and MMP-cleavable crosslinkers were incorporated to facilitate cell adhesion and cell-mediated degradation. Three PDC lines were compared including adult glioblastoma cells (aGBM), pediatric glioblastoma cells (pGBM), and diffuse pontine intrinsic glioma (DIPG). A commonly used immortalized adult glioblastoma cell line U87 was included as a control. PDCs displayed stiffness-dependent behavior, with 40 Pa hydrogel promoting faster tumor proliferation and invasion. Adult GBM cells exhibited faster proliferation than pediatric GBM, and DIPG showed slowest proliferation. These results suggest both patient age and tumor location affects brain tumor behaviors. Adult GBM PDCs also exhibited very different cell proliferation and morphology from U87. The hydrogel reported here can provide a useful tool for future studies to better understand how age and anatomical locations impacts brain tumor progression using 3D in vitro models.
View details for DOI 10.1016/j.actbio.2020.09.007
View details for PubMedID 32911104
- Mimicking brain tumor-vasculature microanatomical architecture via co-culture of brain tumor and endothelial cells in 3D hydrogels BIOMATERIALS 2019; 202: 35–44
Mimicking brain tumor-vasculature microanatomical architecture via co-culture of brain tumor and endothelial cells in 3D hydrogels.
2019; 202: 35–44
Glioblastoma (GBM) is an aggressive malignant brain tumor with median survival of 12 months and 5-year survival rate less than 5%. GBM is highly vascularized, and the interactions between tumor and endothelial cells play an important role in driving tumor growth. To study tumor-endothelial interactions, the gold standard co-culture model is transwell culture, which fails to recapitulate the biochemical or physical cues found in tumor niche. Recently, we reported the development of poly(ethylene-glycol)-based hydrogels as 3D niche that supported GBM proliferation and invasion. To further mimic the microanatomical architecture of tumor-endothelial interactions in vivo, here we developed a hydrogel-based co-culture model that mimics the spatial organization of tumor and endothelial cells. To increase the physiological relevance, patient-derived GBM cells and mouse brain endothelial cells were used as model cell types. Using hydrolytically-degradable alginate fibers as porogens, endothelial cells were deployed and patterned into vessel-like structures in 3D hydrogels with high cell viability and retention of endothelial phenotype. Co-culture led to a significant increase in GBM cell proliferation and decrease in endothelial cell expression of cell adhesion proteins. In summary, we have developed a novel 3D co-culture model that mimics the in vivo spatial organization of brain tumor and endothelial cells. Such model may provide a valuable tool for future mechanistic studies to elucidate the effects of tumor-endothelial interactions on tumor progression in a more physiologically-relevant manner.
View details for PubMedID 30836243
Tissue-engineered 3D Models for Elucidating Primary and Metastatic Bone Cancer Progression.
Malignant bone tumors are aggressive neoplasms which arise from bone tissue or as a result of metastasis. The most prevalent types of cancer, such as breast, prostate, and lung cancer, all preferentially metastasize to bone, yet the role of the bone niche in promoting cancer progression remains poorly understood. Tissue engineering has the potential to bridge this knowledge gap by providing 3D in vitro systems that can be specifically designed to mimic key properties of the bone niche in a more physiologically relevant context than standard 2D culture. Elucidating the crucial components of the bone niche that recruit metastatic cells, support tumor growth, and promote cancer-induced destruction of bone tissue would support efforts for preventing and treating these devastating malignancies. In this review, we summarize recent efforts focused on developing in vitro 3D models of primary bone cancer and bone metastasis using tissue engineering approaches. Such 3D in vitro models can enable the identification of effective therapeutic targets and facilitate high-throughput drug screening to effectively treat bone cancers. STATEMENT OF SIGNIFICANCE: Biomaterials-based 3D culture have been traditionally used for tissue regeneration. Recent research harnessed biomaterials to create 3D in vitro cancer models, with demonstrated advantages over conventional 2D culture in recapitulating tumor progression and drug response in vivo. However, previous work has been largely limited to modeling soft tissue cancer, such as breast cancer and brain cancer. Unlike soft tissues, bone is characterized with high stiffness and mineral content. Primary bone cancer affects mostly children with poor treatment outcomes, and bone is the most common site of cancer metastasis. Here we summarize emerging efforts on engineering 3D bone cancer models using tissue engineering approaches, and future directions needed to further advance this relatively new research area.
View details for DOI 10.1016/j.actbio.2019.08.020
View details for PubMedID 31419564
Co-coating of receptor-targeted drug nanocarriers with anti-phagocytic moieties enhances specific tissue uptake versus non-specific phagocytic clearance
2017; 147: 14–25
Nanocarriers (NCs) help improve the performance of therapeutics, but their removal by phagocytes in the liver, spleen, tissues, etc. diminishes this potential. Although NC functionalization with polyethylene glycol (PEG) lowers interaction with phagocytes, it also reduces interactions with tissue cells. Coating NCs with CD47, a protein expressed by body cells to avoid phagocytic removal, offers an alternative. Previous studies showed that coating CD47 on non-targeted NCs reduces phagocytosis, but whether this alters binding and endocytosis of actively-targeted NCs remains unknown. To evaluate this, we used polymer NCs targeted to ICAM-1, a receptor overexpressed in many diseases. Co-coating of CD47 on anti-ICAM NCs reduced macrophage phagocytosis by ∼50% for up to 24 h, while increasing endothelial-cell targeting by ∼87% over control anti-ICAM/IgG NCs. Anti-ICAM/CD47 NCs were endocytosed via the CAM-mediated pathway with efficiency similar (0.99-fold) to anti-ICAM/IgG NCs. Comparable outcomes were observed for NCs targeted to PECAM-1 or transferrin receptor, suggesting broad applicability. When injected in mice, anti-ICAM/CD47 NCs reduced liver and spleen uptake by ∼30-50% and increased lung targeting by ∼2-fold (∼10-fold over IgG NCs). Therefore, co-coating NCs with CD47 and targeting moieties reduces macrophage phagocytosis and improves targeted uptake. This strategy may significantly improve the efficacy of targeted drug NCs.
View details for DOI 10.1016/j.biomaterials.2017.08.045
View details for Web of Science ID 000413609700002
View details for PubMedID 28923682
View details for PubMedCentralID PMC5667353
- Investigating aging effects for porous silicon energetic materials COMBUSTION AND FLAME 2017; 181: 164–71